NO893653L - QUINOLINE DERIVATIVES AND THEIR PREPARATION. - Google Patents

Description

The present invention relates to quinoline derivatives with the formula

and their manufacture.

In formula I means:

Ri a trifluoromethyl residue, R2 and R3 together with nitrogen the atom they are attached to a morphol no residue and R4 is 4-methyl-phenyl, 2, 3 or 4 fluoro-phenyl, 4-methoxy-phenyl, 4-methyl 3-fluoro-phenyl, 2,4-difluoro-phenyl or 4-amino -phenyl;

or

Rj a trifluoromethyl residue, R 2 and R 3 together with the nitrogen atom they are bound to a thiomorph or ino residue or R 2 a methyl residue and R 3 a 2-methoxy-ethyl residue and R 4 a 4-methyl-phenyl residue; or

Ri means a chlorine or fluorine atom or a methoxy acid residue, R2

and R3 together with the nitrogen to which they are attached means a morphol no residue and R4 means a 4-methyl-phenyl residue.

The compounds of formula I except those where R4 is a 4-amino-phenyl residue can be prepared by reacting a quinoline of the formula: where R1 and R4 have the same meaning as above except that R4 cannot be a 4-amino-phenyl residue, with a compound of the formula:

where R£ and R3 have the same meaning as above and Hal means a halogen atom, preferably chlorine or bromine.

This reaction is preferably carried out in the presence of an alkali metal carbonate such as sodium or potassium carbonate in an organic solution such as a ketone, for example 2-butanone, at a temperature between 20°C and the boiling point of the solvent.

The quinolines of formula II can be obtained by cyclization of a compound of the formula:

where Ri and R4 have the same meaning as above.

This cyclization is generally carried out in an organic solvent such as benzene, toluene or xylene in the presence of sodium tert-butylate at the boiling point of the solvent.

The compounds of formula IV can be obtained by reacting an amine derivative of the formula: where Ri has the same meaning as in formula I or a salt thereof with an acid, with a chlorine compound of the formula:

where R4 has the same meaning as above.

This reaction is preferably carried out in an organic solvent such as benzene, toluene or xylene in the presence of a pyridine at a temperature close to 20°C.

The amine derivative of formula V can be obtained by reacting a compound of the formula:

where Ri has the same meaning as above and then setting the amine group free.

The oxidation can be carried out using a chromic anhydride in a ketone such as acetone at a temperature between -5" and 0°C and the liberation of the amine can take place using an acid such as hydrochloric acid, in an alcohol such as methanol or butanol.

The compounds of formula VII can be prepared by reacting an acetaldehyde with a compound of the formula:

where Ri has the same meaning as in formula I.

This reaction takes place with the help of butyllithium in an organic solvent such as hexane at a temperature between -78°C and 20°C.

The compounds of formula VIII can be obtained by reacting a pivalyl chloride with a compound of the formula:

where Ri has the same meaning as in formula I.

This reaction preferably takes place in an organic solvent such as benzene or toluene in the presence of a trialkylamine or pyridine at a temperature between 0 and 20°C.

The derivatives of formula III in which Ri means a chlorine or fluorine atom can likewise be obtained by reacting a compound of formula IX in which Ri has the same meaning as above and a 4-methyl-benzoyl-acetate of ethyl.

This reaction is generally carried out using phosphoric acid at a temperature between 100 and 170°C. The product is obtained in mixture with 7-fluoro or chlorine 2-(4-methyl-phenyl) 4-quinolone.

This mixture can be used as such for the preparation of a compound of formula I.

The compounds of formula I, except for those where R4 means a 4-amino-phenyl residue, can also be prepared by reacting an acid chloride with the formula: where R^ and R4 have the same meaning as in formula I except that R4 cannot be a 4-amino-phenyl residue, with an amine of the formula:

where R2 and R3 have the same meaning as in formula I.

This reaction is preferably carried out in a chlorinated solvent such as chloroform or methylene chloride in the presence of a tertiary amine such as triethylamine at a temperature between 20°C and the boiling temperature of the solvent.

The acid chlorides of formula X can be obtained by reacting a chlorinating agent such as thionyl chloride on the corresponding acid.

This reaction can be carried out in an inert solvent such as chloroform or toluene, preferably at the boiling temperature of the solvent.

The corresponding acids can be prepared by hydrolysis of the corresponding ethyl esters.

This hydrolysis is generally carried out using an aqueous solution of NaOH at the boiling temperature of the reaction medium.

The ethyl esters can be obtained by reacting a quinolone with formula II and ethyl bromoacetate.

This reaction is preferably carried out in a ketone such as 2-butanone in the presence of an alkali metal carbonate such as potassium or sodium carbonate at the boiling temperature of the solvent.

The compound of formula I where R 4 denotes a 4-amino-phenyl residue can be obtained by reacting 4-[(2-(4-nitro-phenyl 5-trifluoro-methyl 4-quinolyl-oxyacetyl)morpholine.

This reaction is generally carried out using palladium on charcoal and hydrochloric acid in an alcohol such as methanol, ethanol, isopropanol or a mixture thereof.

4[(2-(4-nitrophenyl 5-trifluoromethyl 4-quinolyl)oxyacetyl)-morpholine can be obtained by the method previously described for the preparation of compounds of formula I.

The reaction mixtures obtained by the various processes described above are then treated according to classical physical methods such as evaporation, extraction, distillation, crystallization or chromatography.

The compounds of formula I exhibit interesting pharmacological properties indicating an anxiolytic, hypnotic, anticonvulsant and antiepileptic action.

The compounds show a good affinity in vitro for benzodiazepine receptor sites at concentrations below or equal to 100 nM according to the technique described by J.C. Blanchard and L. Julou, "J. of Neurochemistry," 40, 601

(1983), inspired by the work of Squires and Braestrup in "Nature", 266, 732 (1977).

In mice, at doses below or equal to 25 mg/kg orally, they are shown to be active against convulsions induced by pentetrazole according to the technique similar to that of Everett and Richards, "J. Pharmacol.", 81, 402 (1944).

The compounds of formula I exhibit a low toxicity. The DL5Q value is generally above 300 mg/kg orally in mice.

Of particular interest are compounds of formula I where R^ denotes a trifluoromethyl residue, R 2 and R 3 together with the nitrogen atom to which they are bound form a morpholine ring and R 4 denotes a 4-methyl-phenyl, 4-chlorophenyl, 4-fluoro-phenyl, 4-methoxy-phenyl, 4-methyl 3-fluoro fluoro-phenyl or 2,4-difluoro-phenyl.

The following examples are illustrative and should not limit the invention.

Example 1

To a stirred suspension of 2.4 g of 2(4-methyl-phenyl) 5-trifluoromethyl 4-quinolone and 1.3 g of 4(2-chloro-acetyl) morpholine in 50 cm^ of 2-butanone is added 2.2 g of anhydrous potassium carbonate. Heat to reflux for 3 hours, cool to ambient temperature, i.e. approx. 20°C, remove insoluble substances by filtration, rinse with 2-butanone, combine the organic phases and remove the solvent under reduced pressure. After recrystallization of the residue from acetonitrile, 2 is isolated, 6 g of 4-[(2(4-methyl-phenyl) 5-trifluoromethyl 4-quinolyl) oxyacetyl morpholine which melts at 172°C.

2-(4-methyl-phenyl) 5-trifluoromethyl 4-quinolone can be prepared in the following way: 2.8 g of N-(2-acetyl 3-trifluoromethyl-phenyl) 4-methyl-benzamide are heated to reflux for 1 hour and 1.07 g of potassium tert-butylate in 30 cm^ of toluene. Cool to a temperature close to 20°C, add 0.55 cm^ of glacial acetic acid and dilute with 30 cm^ of water and 15 cm^ of ethyl ether. The suspension is stirred for 30 minutes, the precipitate is poured off, washed twice with ethyl ether and then with water and finally dried. This exhibits a melting point of over 260°C.

N-(2-acetyl 3-trifluoromethyl-phenyl) 4-methyl-benzamide can be prepared in the following way: stirring at approx. 20°C and for 45 minutes 2.39 g of 2-amino 6-trifluoromethyl-acetophenone hydrochloride, 1.45 cm<3>4-methyl-benzoyl chloride and 1.7 cm<3>pyridine in 20 cm<3 >anhydrous toluene. 20 cm<3> of water and 80 cm<3> of ethyl acetate are then added. The aqueous phase is decanted and the organic phase is washed three times with 25 cm<3> of water, dried over magnesium sulphate and evaporated under reduced pressure. The obtained residue is stirred in 50 cm<3> of petroleum ether, filtered and washed with petroleum ether. This happens twice. In this way, 2.5 g of N-(2-acetyl 3-trifluoromethyl-phenyl) 4-methyl-benzamide with a melting point of 171°C are isolated.

2-amino 6-trifluoromethyl acetophenone can be prepared in the following way: 67 g of N-(2-acetyl 3-trifluoromethyl-phenyl) 2,2-dimethyl propionamide is heated to reflux for 5 hours and 30 minutes in a mixture of 670 cm< 3>concentrated hydrochloric acid and 670 cm<3>ethanol. It is cooled to about 20°C. The solvents are evaporated under reduced pressure, the crystallized residue is taken up several times in toluene and evaporated each time to remove residual water, the whole is washed with ethyl ether and then with petroleum ether at 40-60° and finally dried under reduced pressure. In this way, 50.4 g of 2-amino 6-trifluoromethyl acetophenone hydrochloride with a melting point of 163°C is obtained.

N-(2-acetyl 3-trifluoromethyl phenyl) 2,2-dimethyl-propionamide can be prepared as follows: a solution, cooled to

-5°C, 36 g of N-(2-(α-hydroxyethyl) 3-trifluoromethyl-phenyl) 2,2-dimethyl-propionamide in 1000 m<3>acetone are added in portions and in the course of 20 minutes 37 g of chromic acid -anhydride. The mixture is stirred for 15 minutes at -5°C and then 19 g of additional chromic anhydride are added in portions. The stirring is continued for a further 15 minutes at -5°C and then slowly introduced at this temperature 120 cm<3>isopropanol to destroy the excess of chromic anhydride. The temperature is allowed to rise to approx. 20°C and evaporates the solvent under reduced pressure. The residue is taken up in 700 cm<3> of water and 1,000 cm<3> of ethyl ether and then stirred for one hour. Some insoluble material is then removed by filtration, which is washed with water and ethyl ether. The

aqueous and organic phases are combined, the aqueous phase is decanted and washed twice with 200 cm<3>ethyl ether. The organic phases are combined, washed with 2 times 100 cm<3> of water, 2 times 100 cm<3> of a 5# potassium bicarbonate solution and 2 times with 100 cm<3> of water, dried over magnesium sulfate and evaporated under reduced pressure. In this way, 34.3 g of N-(2-acetyl 3-trifluoromethyl-phenyl) 2,2-dimethyl-propionamide with a melting point of 142°C is obtained.

N-(2(α-hydroxyethyl) 3-trifluoromethyl-phenyl) 2,2-dimethyl-propionamide can be prepared in the following way: to a solution of 7.7 g of N-(3-trifluoromethyl-phenyl) 2,2 -dimethyl-propionamide in 40 cm<3> of dry tetrahydrofuran is placed under a nitrogen atmosphere and cooled to 10° C, during 15 minutes, 45 cm<3> of a 1.37 M solution of n-butyllithium in hexane and the whole stirred for 2 hours at this temperature. The solution is then cooled to -78°C and 17.5 cm<3>acetaldehyde cooled to -78°C is added at once. The temperature rises quickly to 12° C and then drops again. When the reaction medium has reached -10" C, 150 cm<3> of water is quickly added. After evaporation of tetrahydrofuran under reduced pressure, the suspension is taken up in 200 cm<3> of ethyl ether and stirred to dissolve. The aqueous phase is decanted, the organic phase is washed with three times 20 cm<3> of water, dried over magnesium sulfate and evaporated under reduced pressure. The residue obtained is taken up in 100 cm<3> of petroleum ether 40-60° and treated under reflux. The clear solution is cooled, the precipitate is poured off , is brought up twice in petroleum ether, washed with isopropyl ether which has previously been cooled to -70° C. and then dried under reduced pressure. In this way, 6.2 g of N-(2-(α-hydroxyethyl) 3-trifluoro -methyl-phenyl) 2,2-dimethyl-propionamide with melting point 172°C.

N-(3-trifluoromethyl-phenyl) 2,2-dimethyl-propionamide can be prepared as follows: to a solution of 130 g of 3-trifluoromethyl-aniline in 1,300 cm<3>toluene, under a nitrogen atmosphere, 118 cm<3>triethylamine is added . After cooling to 10°C, 105 cm<3>pivaloyl chloride is introduced over 45 minutes and the mixture is stirred at a temperature close to 20°C for one hour. The suspension is taken up in 500 cm<3>water and 300 cm<3>ethyl acetate. The organic phase is decanted and the aqueous phase is washed with 200 cm<3>ethyl acetate.The organic phases are combined, washed with 300 cm<3>water, 200 cm<3>of an aqueous solution of hydrochloric acid and then with 200 cm<3> water and dried over magnesium sulfate. The solvent is removed under reduced pressure. The residue obtained is taken up with 3 times 100 cm3 of petroleum ether 40-60° and then dried. In this way, 183.4 g of N-(3- trifluoromethyl-phenyl) 2,2-dimethyl-propionamide with melting point 107°C.

Example 2

One works as in example 1, but starts from 2.39 g of 2-(4-chloro-phenyl) 5-trifluoromethyl 4-quinolone, 1.62 g of 4-(2-chloro-acetyl) morpholine and 2.5 g anhydrous potassium carbonate in 60 cm<3>2-butanone. After recrystallization from acetonitrile, 3.2 g of 4-[(2-(4-chloro-phenyl) 5-trifluoromethyl 4-quinolyl) oxyacetyl] morpholine with a melting point of 179°C is isolated.

2-(4-chloro-phenyl) 5-trifluoromethyl 4-quinolone can be prepared in the following way: one works in the same way as in example 1 for the preparation of 2-(4-methyl-phenyl) 5-trifluoromethyl 4-quinolone from 3.5 g of N-(2-acetyl 3-trifluoromethyl-phenyl) 4-chloro-benzamide and 1.24 g of potassium tert-butylate in 40 cm<3>toluene, the heating is continued for 1 hour and 30 minutes. The compound has a melting point of over 260°C.

N-(2-acetyl 3-trifluoromethyl-phenyl) 4-chloro-benzamide can be prepared in the following way: work as in example 1 for the preparation of N-(2-acetyl 3-trifluoromethyl-phenyl) 4-methyl-benzamide out from 2.7 g of 2-amino 6-trifluoromethyl-aceto-phenone hydrochloride, 1.58 cm<3>4-chloro-benzoyl chloride and 2 cm<3>pyridine in 30 cm<3>anhydrous toluene, but extending the reaction time to 2 hours . The compound has a melting point equal to 210°C.

Example 3

One works as in example 1, but starts from 2.6 g of 2-(4-fluoro-phenyl) 5-trifluoromethyl 4-quinolone, 1.53 g of 4-(2-chloro-acetyl) morpholine and 2.35 g anhydrous potassium carbonate in 60 cm<3>2-butanone. After recrystallization from isopropyl ether:acetonitrile (37:10 by volume) 3.2 g of 4-[(2-(4-fluoro-phenyl) 5-trifluoromethyl 4-quinolyl) oxaacetyl] morpholine with melting point 164°C is isolated.

2-(4-fluoro-phenyl) 5-trifluoromethyl 4-quinolone can be prepared in the following way: work as in example 1 for the production of 2-(4-methyl-phenyl) 5-trifluoromethyl 4-quinolone from 3 g of N -(2-acetyl 3-trifluoromethyl-phenyl) 4-fluoro-benzamide and 1.13 g of potassium tert-butylate in 40 cm<3>toluene while extending the reaction time to 2 hours. The product has a melting point of over 260°C.

N-(2-acetyl 3-trifluoromethyl-phenyl) 4-fluoro-benzamide can be prepared in the following way: work as in example 1 for the preparation of N-(2-acetyl 3-trifluoromethyl-phenyl) 4-methyl-benzamide out from 2.7 g of 2-amino 6-trifluoromethyl-acetophenone hydrochloride, 1.49 cm<3>4-fluoro-bezoyl chloride and 2 cm<3>pyridine in 30 cm<3>anhydrous toluene extending the reaction time to 2 hours. The compound has a melting point equal to 200°C.

Example 4

One works as in example 1, but starts from 2.6 g of 2-(2-fluoro-phenyl) 5-trifluoromethyl 4-quinolone, 1.53 g of 4-(2-chloro-acetyl morpholine) and 2.35 g of anhydrous potassium carbonate in 60 cm<3>2-butanone, extending the reaction time to 4 hours and 30 minutes. After recrystallization from isopropyl ether:acetonitrile in the volume ratio 37:16, 3.2 g of 4-[(2-(2-fluoro-phenyl) 5-trifluoromethyl (4-quinolyl)oxyacetyl]morpholine with a melting point of 172"C.

2-(2-Fluoro-phenyl) 5-trifluoromethyl 4-quinolone can be prepared in the following way: one works as in example 1 for the preparation of 2-(4-methyl-phenyl) 5-trifluoromethyl 4-quinolone from 3,2 g of N-(2-acetyl 3-trifluoromethyl-phenyl) 2-fluorobenzamide and 1.2 g of potassium tert-butylate in 40 cm<3>toluene, extending the reaction time to 2 hours. The compound exhibits a melting point of over 260°C.

N-(2-acetyl 3-trifluoromethyl-phenyl) 2-fluoro benzamide can be prepared in the following way: one works as in example 1 for the preparation of N-(2-acetyl 3-trifluoromethyl-phenyl) 4-methyl benzamide from 2 .7 g of 2-amino 6-trifluoromethyl acetophenone hydrochloride, 1.5 cm<3>2-fluoro-benzyl chloride and 2 cm<3>pyridine in 30 cm<3>anhydrous toluene. The compound has a melting point equal to 100°C.

Example 5

One works as in example 1, but starts from 2.9 g of 2-(4-methoxy-phenyl) 5-trifluoromethyl 4-quinolone, 1.64 g of 4-(2-chloro-acetyl) morpholine and 2.50 g anhydrous potassium carbonate in 60 cm<3>2-butanone. After recrystallization from acetonitrile, 3.2 g of 4-[(2-(4-methoxy-phenyl) 5-trifluoromethyl 4-quinolyl) oxyacetyl] morpholine with melting point 175°C is isolated.

2-(4-Methoxy-phenyl) 5-trifluoromethyl 4-quinolone can be prepared in the following way: one works as in example 1 for the preparation of 2-(4-methyl-phenyl) 5-trifluoromethyl 4-quinolone from 3.34 g of N-(2-acetyl 3-trifluoromethyl-phenyl) 4-methoxy-benzamide and 1.22 g of potassium tert-butylate in 40 cm<3>toluene, extending the reaction time to 6 hours. The compounds have a melting point of over 260°C.

N-(2-acetyl 3-trifluoromethyl-phenyl) 4-methoxy-benzamide can be prepared in the following way: one works as in example 1 for the preparation of N-(2-acetyl 3-trifluoromethyl-phenyl) 4-methyl-benzamide out from 2.7 g of 2-amino 6-trifluoromethyl acetophenone hydrochloride, 1.75 cm<3>4-methoxy-benzoyl chloride and 2 cm<3>pyridine in 30 cm<3>anhydrous toluene extending the reaction time to 2 hours. The compound has a melting point equal to 171°C.

Example 6

One works as in example 1, but starts from 2.6 g of 2-(4-methyl 3-fluoro-phenyl) 5-trifluoromethyl 4-quinolone, 1.46 g of 4-(2-chloro-acetyl) morpholine and 2 .2 g of anhydrous potassium carbonate in 60 cm<3>2-butanone. After recrystallization from isopropyl ether:-acetonitrile in the volume ratio 34:9, 2.7 4-[(2-(4-methyl 3-fluoro-phenyl) 5-trifluoromethyl 4-quinolyl) oxyacetyl] morpholine with melting point 169°C is isolated.

2-(4-methyl 3-fluoro-phenyl) 5-trifluoromethyl 4-quinolone can be prepared in the following way: one works as in example 1 for the preparation of 2-(4-methyl-phenyl) 5-trifluoromethyl 4-quinolone from 2.9 g of N-(2-acetyl 3-trifluoromethyl-phenyl) 4-methyl 3-fluoro-benzamide and 1.06 g of potassium tert-butylate in 40 cm<3>toluene. The compounds have a melting point of over 260°C.

N-(2-acetyl 3-trifluoromethyl-phenyl) 4-methyl 3-fluoro-benzamide can be prepared in the following way: work as in example 1 for the preparation of N-(2-acetyl 3-trifluoromethyl-phenyl) 4-methyl -benzamide from 2.7 g of 2-amino 6-trifluoromethyl acetophenone hydrochloride, 2.32 g of 4-methyl 3-fluoro benzoyl chloride and 2 cm<3>pyridine in 30 cm<3>anhydrous toluene. The compound has a melting point equal to 164°C.

Example 7

One works as in example 1, but starts from 1.8 g of 2-(3-fluoro-phenyl) 5-trifluoromethyl 4-quinolone, 1.06 g of 4-(2-chloro-acetyl) morpholine and 1.60 g anhydrous potassium carbonate in 36 cm<3>2-butanone. The residue of 2.35 g is dissolved hot in 25 cm<3>ethyl acetate and the solution is filtered hot. 25 cm<3> of petroleum ether 40-60° are added and the solid that precipitates is separated by filtration and dried. 1.77 g of 4-[(2-(3-fluoro-phenyl) 5-trifluoromethyl 4-quinolyl) oxyacetyl] morpholine with a melting point of 157°C is isolated.

2-(3-Fluoro-phenyl) 5-trifluoromethyl 4-quinolone can be prepared in the following way: one works as in example 1 for the preparation of 2-(4-methyl-phenyl) 5-trifluoromethyl 4-quinolone from 2.56 g of N-(2-acetyl 3-trifluoromethyl-phenyl) 3-fluoro-benzamide and 0.97 g of potassium tert-butylate in 26 cm<3>toluene, extending the reaction time to 2 hours and 30 minutes. The compounds have a melting point of over 260°C.

N-(2-acetyl 3-trifluoromethyl-phenyl) 3-fluoro-benzamide can be prepared in the following way: work as in example 1 for the preparation of N-(2-acetyl 3-trifluoromethyl-phenyl) 4-methyl-benzamide out from 2.3 g of 2-amino 6-trifluoromethyl acetophenone hydrochloride, 1.68 g of 3-fluoro benzoyl chloride and 1.7 cm<3>pyridine in 26 cm<3>anhydrous toluene extending the reaction time to 2 hours. The compound has a melting point equal to 150°C.

Example 8

To a stirred suspension of 10 g of a mixture of 5-chloro 2-(4-methyl-phenyl) 4-quinolone and 7-chloro 2-(4-methyl-phenyl) 4-quinolone and 10.2 g of anhydrous potassium carbonate in 250 cm<3>2-butanone, 7.9 g of 4-(2-bromo-acetyl)morpholine are added to 50 cm<3>2-butanone. It is heated to reflux for 15 hours, cooled to approx. 20° C, removes insoluble substances by filtration and evaporates 2-butanone under reduced pressure. The residue is taken up in 200 cm<3> of water and the aqueous phase is extracted 3 times with 100 cm<3> of methylene chloride. The organic phase is decanted, dried and evaporated under reduced pressure. After two chromatographs of the residue on silica gel, the first with chloroform:ethyl acetate in the volume ratio 70:30 and the second with chloroform:ethyl acetate in the volume ratio 80:20 as eluent, the solid residue is recrystallized from ethyl acetate. In this way, 2 g of 4-[(5-chloro 2-(4-methyl-phenyl) 4-quinolyl) oxyacetyl] morpholine with a melting point of 170°C is obtained.

The mixture of 5-chloro 2-(4-methyl-phenyl) 4-quinolone and 7-chloro 2-(4-methyl-phenyl) 4-quinolone can be obtained in the following way: heating to 150°C for 20 minutes and under stirring 13 g of 3-chloroaniline and 41.2 g of 4-methyl ethyl bezoyl acetate in 40 g of polyphosphoric acid. The whole is then cooled to 90°C, 10 cm<3> of concentrated hydrochloric acid and then 100 cm<3> of water are added. The precipitate is poured off, washed with 3 times 100 cm<3>water, 2 times 50 cm<3>ethyl ether and 2 times 50 cm<3>acetone. In this way, 30 g of a mixture of 5-chloro 2-(4-methyl-phenyl) 4-quinolone and 7-chloro 2-(4-methyl-phenyl) quinolone is obtained, which is used as such in the later syntheses.

Example 9

To a stirred suspension of 2.9 g of 2-(4-methyl-phenyl) 5-methoxy 4-quinolone and 1.62 g of 4-(2-chloro-acetyl) morpholine in 76 cm<3>2-butanone is added 2 .28 g anhydrous potassium carbonate. It is heated to reflux for 4 hours and 20 minutes, cooled to approx. 20" C and evaporates the solvent under reduced pressure. The residue is taken up with water and ethyl acetate, the organic phase is decanted, dried over magnesium sulfate and evaporated under reduced pressure. The residue obtained is chromatographed over silica gel using chloroform:acetone in the volume ratio 95:5. The recovered solid is stirred in 50 cm<3>petroleum ether 40-60". One thus isolates 2.3 g of 4-[(2-(4-methyl-phenyl) 5-methoxy 4-quinolyl) oxyacetyl] morpholine with a melting point of 132°C.

2-(4-methyl-phenyl) 5-methoxy 4-quinolone can be prepared in the following way: one heats under reflux and for 1 hour 2.27 g of N-(2-acetyl 3-methoxy-phenyl) 4-methyl-benzamide and 1.36 g of potassium tert-butylate in 23 cm<3>toluene. Cool to approx. 20°C, add 1.5 cm<3>glacial vinegar and dilute with 25 cm<3>water. The suspension is stirred for 15 minutes, the precipitate is poured off, washed with water, toluene, petroleum ether at 40-60° and dried. The product has a melting point of 207<0>C.

N-(2-acetyl 3-methoxy-phenyl) 4-methyl-benzamide can be prepared in the following way: stirring at approx. 20°C and for 1 hour 20 minutes 4 g of 2-amino 6-methoxy acetophenone, 3.5 cm<3>4-methyl benzoyl chloride and 2.15 cm<3>pyridine in 40 cm<3>anhydrous toluene. 40 cm<3> of water and 60 cm<3> of toluene are then added. The aqueous phase is decanted, the organic phase is washed three times with 25 cm<3> of water, dried over magnesium sulphate and evaporated under reduced pressure. The obtained residue is stirred in 75 cm<3>petroleum ether 40-60° and 25 Cl113 ethyl acetate, filtered and washed with petroleum ether at 40-60°. In this way, 2.44 g of N-(2-acetyl 3-methoxy-phenyl) 4-methyl-benzamide with a melting point of 48°C is isolated.

2-amino 6-methoxy-acetophenone can be prepared in the following way: 18 g of N-(2-acetyl 3-methoxy-phenyl) 2,2-dimethyl-propionamide are heated under reflux for 4 hours and 40 minutes in a mixture of 90 cm<3>concentrated hydrochloric acid and 90 cm<3>ethanol. Cool to approx. 20°C, add 100 cm<3>ethyl acetate and 250 cm<3>of a saturated potassium carbonate solution. The aqueous phase is extracted with ethyl acetate and the organic phase is washed with water. The organic phases are combined, dried over magnesium sulphate and evaporated under reduced pressure. The obtained oil is used as such in the later syntheses.

N-(2-acetyl 3-methoxy-phenyl) 2,2-dimethyl-propionamide can be prepared as follows: to a solution cooled to 0°C of 35 g of N-(2-(α-hydroxyethyl) 3-methoxy-phenyl ) 2,2-dimethyl-propionamide in 525 cm<3>acetone is added portionwise during

40 minutes 41 g chromic anhydride. The mixture is stirred for 1 hour and 5 minutes at 0°C and then a further 21 g of chromic anhydride is added. Stirring is continued for 1 hour and 45 minutes at 0°C and then at this temperature 160 cm<3>isopropanol is slowly added to destroy excess chromic anhydride. The temperature is allowed to rise to approx. 20°C and evaporates the solvent under reduced pressure. The residue is taken up in 500 cm<3>ethyl acetate and stirred at ambient temperature. The solid is removed by filtration and washed with 350 cm<3>ethyl acetate. The organic phase is concentrated under reduced pressure and the residue is chromatographed on silica gel using methylene chloride acetate 99:1. One thus isolates 7.83 g of N-(2-acetyl 3-methoxy-phenyl) 2,2-dimethyl-propionamide which melts below 40°C.

N-(2-(a-hydroxyethyl) 3-methoxy-phenyl) 2,2-dimethyl-propionamide can be prepared as follows: to a solution of 10 g of N-(3-methoxy-phenyl) 2,2-dimethyl-propionamide in 150 cm<3> of dry tetrahydrofuran is placed under a nitrogen atmosphere and while cooling to 0°C during 25 minutes 90.5 cm<3> of a 1.37 M solution of n-butyllithium in hexane and the whole is stirred for 2 hours at this temperature. The solution is then cooled to -78°C and 27 cm<3>acetaldehyde cooled to -78°C is added at once. The temperature rises rapidly to 4°C and then falls. After the temperature has dropped to -10°C, rapid addition 57 cm<3>water and 200 cm<3>ethyl ether. After separation of the phases by decantation, the aqueous phase is extracted with ethyl ether, the organic phases are combined and evaporated. To the obtained residue is added 100 cm<3>isopropyl ether, triturated the residue which crystallizes, then add 100 cm<3>petroleum ether at 40-60° and stir for 15 minutes. The treatment is repeated with 50 cm<3>petroleum ether at 40-60° and 50 cm<3>isopropyl ether. After filtration and drying, obtain 9.65 g of N-(2-(c-hydroxyethyl)3-methoxy-phenyl)2,2-dimethyl-propionamide with melting point 159°C.

N-(3-methoxy-phenyl) 2,2-dimethyl-propionamide can be prepared as follows: to the stirred solution of 110.7 g of 3-methoxy-aniline in 1,100 cm<3>toluene is added 79.7 cm<3 >pyridine and then slowly 120.5 cm<3>pivaloyl chloride. Stir for 1 hour and 15 minutes at a temperature close to 20° C and then add 500 cm<3> of water. The precipitate is poured off, washed with water and toluene and dried at 70°C under reduced pressure in the presence of sodium hydroxide lozenges. In this way, 137.4 g of N-(3-methoxy-phenyl) 2,2-dimethyl-propionamide with a melting point of 126°C is obtained.

Example 10

To a stirred solution of 3 g of 2-(4-methyl-phenyl) 5-trifluoro-methyl 4-quinolone oxyacetic acid in 90 cm<3>chloroform is slowly added 1.8 cm<3>thionyl chloride. It is heated for 3 hours under reflux, the solvent and thionyl chloride are evaporated under reduced pressure, the whole is taken up twice in chloroform and evaporated each time to remove traces of thionyl chloride. The obtained residue is brought into suspension in 90 cm<3>chloroform, the solution is cooled to 10" C and 2.2 cm<3>triethylamine is added. Still at this temperature, a solution of 0.8 cm<3>thiomorpholine in 10 cm<3>chloroform. Stir for 15 hours at ambient temperature, evaporate the solvent under reduced pressure, take up the residue in 100 cm<3>ethyl acetate and 60 cm<3>water. The organic phase is decanted, washed with 50 cm<3 >water, twice 20 cm<3>of a decinormal solution of sodium hydroxide and finally with 20 cm<3>water, then dried over magnesium sulfate After evaporation of the solvent under reduced pressure, a residue of 3.3 g is isolated and chromatographed on a silica gel column using methylene chloride: ethyl acetate in the volume ratio 95:5 as eluent. The residue obtained is stirred in 30 cm<3>petroleum ether at 40-60° and in this way 1.9 g of 4-[(2 -(4-methyl-phenyl) 5-trifluoromethyl 4-quinolyl)oxyacetyl]thiomorpholine with melting point 154°C.

2-(4-methyl-phenyl) 5-trifluoromethyl 4-quinolone oxyacetic acid can be prepared in the following way: heat to reflux and for 10 hours 28.6 g of ethyl 2-(4-methyl-phenyl) 5-trifluoromethyl 4-quinolyl oxyacetate and 115 cm<3> of a sodium hydroxide solution in 700 cm<3> of water. It is cooled to ambient temperature, acidified to pH 5 by adding 7 cm<3>glacial vinegar and stirred for 1 hour and 30 minutes at 10°C. The precipitate is poured off, washed with water and dried. 25.6 g of 2-(4-methyl-phenyl) 5-trifluoromethyl 4-quinolyl oxyacetic acid are obtained (Rf=0.22; chromatography on a silica gel plate, ethyl acetate as eluent).

2-(4-methyl-phenyl) 5-trifluoromethyl 4-quinolyl oxyacetate can be prepared in the following way: 24.5 g of 2-(4-methyl-phenyl) 5-trifluoro-methyl are heated for 3 hours and 30 minutes to reflux 4-quinolone, 9.9 cm<3>ethyl bromoacetate and 23.4 g anhydrous potassium carbonate in 730 cm<3>2-butanone. Cool to 20° C, pour insoluble material over a frit and wash several times with ethyl ether. The organic phases are evaporated under reduced pressure and the residue obtained is taken up in 250 cm3 of petroleum ether at 40-60° and heated under reflux. The suspension is then cooled to 10°C with rapid stirring for 30 minutes. The precipitate is poured off, washed with some petroleum ether at 40-60° and dried. 28.1 g of ethyl 2-(4-methyl-phenyl 5-trifluoromethyl 4-quinolyl oxyacetate with a melting point of 134°C are obtained in this way.

Example 11

To a stirred suspension of 3 g of 2-(4-methyl-phenyl) 5-trifluoromethyl 4-quinolyl oxyacetic acid as prepared in example 8 in 100 cm<3>chloroform is slowly added 3 cm<3>thionyl chloride. One heats for 3 hours under reflux, evaporates the solvent and thionyl chloride under reduced pressure, takes up twice in chloroform and evaporates each time to remove traces of thionyl chloride. The obtained residue is brought into suspension in 100 cm<3>chloroform, the solution is cooled to 10°C and 3 cm<3>triethylamine is introduced. Still at this temperature, a solution of 1.25 g of N-(2-methoxyethyl)N-methylamine in 10 cm<3>chloroform is added. Stir for 15 hours at approx. 20°C, evaporate the solvent under reduced pressure, take up the residue in 100 cm<3>ethyl ether and 30 cm<3>water. The organic phase is decanted, washed with 30 cm<3> of water, twice with 20 cm<3> of a decinormal sodium hydroxide solution and twice with 20 cm<3> of water, and then dried over magnesium sulfate. After evaporation of the solvents under reduced pressure, a residue of 1.9 g is isolated which is chromatographed on silica gel with methylene chloride:ethyl acetate in the volume ratio 95:5 as eluent. The obtained residue is stirred in 20 cm<3> of petroleum ether at 40-60°. 1 g of N-methyl N-(2-methoxyethyl) (2-(4-methyl-phenyl) 5-trifluoromethyl 4-quinolyl) oxyacetamide with a melting point of 116°C is obtained in this way.

Example 12

One works as in example 1, but starts from 2.3 g of 2-(2,4-difluoro-phenyl) 5-trifluoromethyl 4-quinolone, 1.35 g of 4-(2-chloro-acetyl) morpholine and 2, 3 g anhydrous potassium carbonate in 70 cm<3>2-butanone and extends the reaction time to 5 hours. After recrystallization from acetonitrile, 2.3 g of 4-[(2-(2,4-difluoro-phenyl) 5-trifluoromethyl 4-quinolyl) oxyacetyl] morpholine with a melting point of 184°C is isolated.

2-(2,4-difluoro-phenyl) 5-trifluoromethyl 4-quinolone can be prepared in the following way: one works as in example 1 for the preparation of 2-(4-methyl-phenyl) 5-trifluoromethyl 4-quinolone from 3 .4 g of N-(2-acetyl 3-trifluoromethyl-phenyl) 2,4-difluoro-benzamide and 1.3 g of potassium tert-butylate in 40 cm<3>toluene, extending the reaction time to 2 hours and 30 minutes. The compounds have a melting point of over 260°C.

N-(2-acetyl 3-trifluoromethyl-phenyl) 2,4-difluoro-benzamide can be prepared in the following way: one works as in example 1 for the preparation of N-(2-acetyl 3-trifluoromethyl-phenyl) 4-methyl- benzamide from 3 g of 2-amino 6-trifluoromethyl acetophenone hydrochloride as prepared in example 1, 2.29 g of 2,4-difluoro benzoyl chloride and 2.2 cm<3>pyridine in 35 cm<3>anhydrous toluene. The compound exhibits an Rf value equal to 0.61 (chromatography on a silica gel plate, eluent: cyclohexane:ethyl acetate in the volume ratio 50:50).

Example 13

To a stirred suspension of 11.2 g of a mixture of 5-fluoro 2-(4-methyl-phenyl) 4-quinolone and 7-fluoro 2-(4-methyl-phenyl) 4-quinolone and 11.3 g of anhydrous potassium carbonate in 250 cm<3>2-butanone, add 7.3 g of 4-(2-bromo-acetyl)morpholine in 50 cm<3>2-butanone. It is heated under reflux for 15 hours, cooled to approx. 20° C, removes insoluble substances by filtration and evaporates 2-butanone under reduced pressure. The residue is taken up in 200 cm<3> of water and the aqueous phase is extracted 3 times with 100 cm<3> of methylene chloride. The organic phase is decanted, dried and evaporated under reduced pressure. After chromatography of the residue on silica gel using cyclohexane:ethyl acetate in the volume ratio 70:30 as eluent, the obtained solid is triturated in 100 cm<3>petroleum ether at 40-60°C. In this way, 2.4 g of 4-[2-(5-fluoro (4-methyl-phenyl) 4-quinolyl)oxyacetyl] morpholine with a melting point of 142-4°C is obtained.

The mixture of 5-fluoro 2-(4-methyl-phenyl) 4-quinolone and 7-fluoro 2-(4-methyl-phenyl) 4-quinolone can be prepared in the following way: It is heated to 150°C for 30 minutes under good stirring 7.3 g of 3-fluoro aniline and 26.7 g of ethyl 4-methyl benzoyl acetate in 27 g of polyphosphoric acid. It is then cooled to 90° C and 60 cm<3> of hydrochloric acid is added. The precipitate is poured off, washed 3 times with 60 cm<3> of water and then 3 times with 60 cm<3> of ethyl ether and finally with 2 times of 50 cm<3> of acetone. 22.9 g of a mixture of 5-fluoro 2-(4-methyl-phenyl) 4-quinolone and 7-fluoro 2-(4-methyl-phenyl) 4-quinolone is thus obtained, which is used as such in the following steps.

Example 14

6.6 g of 4-[(2-(4-nitro-phenyl) 5-trifluoromethyl 4-quinolyl)oxyacetyl] morpholine in solution in 132 cm<3>methanol are hydrogenated for 3 hours and 30 minutes under atmospheric pressure in the presence of 6.6 cm<3> of an 8N gaseous hydrochloric acid solution in isopropanol and 0.66 g of 10% palladium on charcoal. 240 cm<3> of distilled water is then added, stirred for 10 minutes and then filtered off the catalyst. 45 cm<3> of an aqueous sodium hydroxide solution is added, the precipitate is filtered, washed 3 times with 100 cm<3> of distilled water and the whole is dried under reduced pressure. The precipitate is dissolved hot in cyclohexane:ethyl acetate in the volume ratio 50:50. The solution is filtered and the filtrate is concentrated under reduced pressure. The residue is taken up in petroleum ether, filtered and dried. 3.16 g of 4-[(2-(4-amino-phenyl) 5-trifluoromethyl 4-quinolyl)oxyacetyl] morpholine with a melting point of 174<0>C are thus obtained.

4-[(2-(4-nltro-phenyl) 5-trifluoromethyl 4-quinolyl)oxyacetyl] morpholine can be prepared in the following way: one works as in example 1 for the preparation of 4-[(2-(4-methyl-phenyl ) 5-trifluoromethyl 4-quinolyl )oxyacetyl] morpholine from 8 g 2-(4-nitro-phenyl) 4-trifluoromethyl 4-quinolone, 6.6 g anhydrous potassium carbonate and 4.3 g 4-(2-chloro-acetyl ) morpholine in 160 cm<3>2-butanone. After recrystallization from 2-butanone, 6.2 g of 4-[(2-(4-nitro-phenyl) 5-trifluoromethyl 4-quinolyl)oxyacetyl] morpholine with melting point 222°C is obtained.

2-(4-nitro-phenyl) 5-trifluoromethyl 4-quinolone can be prepared as follows: one works as in example 1 for the preparation of 2-(4-methyl-phenyl) 5-trifluoromethyl 4-quinolone from 10.6 g N-(2-acetyl 3-trifluoromethyl-phenyl) 4-nitro-benzamide and 3.7 g of potassium tert-butylate in a mixture of 106 cm<3>toluene and 10 cm<3>dimethylformamide. 8.15 g of 2-(4-nitro-phenyl) 5-trifluoromethyl 4-quinolone is obtained which melts below 260°C.

N-(2-acetyl 3-trifluoromethyl-phenyl) 4-nitro-benzamide can be prepared in the following way: work as in example 1 for the preparation of N-(2-acetyl 3-trifluoromethyl-phenyl) 4-methyl-benzamide out from 10 g of 2-amino 6-trifluoromethyl acetophenone hydrochloride and 10.1 g of 4-nitrobenzoic acid chloride in a mixture of 100 cm<3>toluene and 8.4 cm<3>pyridine. 10.8 g of N-(2-acetyl 3-trifluoromethyl-phenyl) 4-nitrobenzamide with a melting point of 2450C are thus obtained.

The invention likewise relates to medicaments containing the compounds of formula I in pure state or in the form of preparations in which they are combined with additives, diluents and/or other pharmaceutically acceptable and compatible carriers. The drugs can be used orally, rectally, parenterally or percutaneously.

Solid preparations for oral administration can be used

tablets, pills, powders (generally in gelatin capsules) or granules. In these preparations, the active ingredient according to the invention is mixed with one or more inert diluents such as sucrose, lactose, starch, cellulose or silicon dioxide. The preparations can likewise comprise substances other than the emollients, for example lubricants such as magnesium stearate or talc, dyes, coating substances or a varnish.

As liquid preparations for oral administration, one can use pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs containing inert diluents such as water, ethanol, glycerol, vegetable oils or paraffin oil. The preparations may also include substances other than the diluents, for example wetting agents, flavourings, odorants, thickeners or stabilisers.

The preparations according to the invention for parenteral administration can be sterile aqueous or non-aqueous solutions, suspensions or emulsions. Propylene glycol, polyethylene glycol, vegetable oils and especially olive oil, injectable organic esters such as ethyl oleate can be used as a solvent or carrier. The preparations may also contain additives and especially wetting agents, isotonic agents, emulsifying, stabilizing and dispersing agents. Sterilization can take place in several ways, for example by means of a bacteriological filter, by incorporating sterilizing agents, by irradiation or heating. They can also be produced in the form of solid sterile preparations that can be dissolved at the time of use in sterile water or another injectable sterile medium.

The preparations for rectal administration are suppositories or rectal capsules which, in addition to the active ingredient, may contain laxatives such as cocoa butter, suppo-wax, semi-synthetic glycerides or polyethylene glycols.

The preparations for percutaneous administration are creams, ointments, lotions and liniments in which the active ingredient is associated with liquid or pasty emollients, preferably in connection with a carrier that favors percutaneous migration.

The medicines and preparations according to the invention are used in particular in human therapy because of the anxiolytic, hypnotic, anticonvulsant and antiepileptic effects.

In human therapy, the dosage depends on the intended effect and the duration of the treatment, usually between 10 and 500 mg per day. day orally for an adult with unit doses from 2 to 100 mg of active ingredient. In general, the doctor determines the dosage as a function of age, weight and all other significant factors.

The following examples shall illustrate preparations according to the invention:

Example A

Gel pills with doses of 50 mg of active ingredient and with the following composition are produced according to usual techniques:

Example B

According to usual techniques, tablets with 50 mg of active ingredient and with the following compositions are produced:

Example C

An injectable solution is prepared containing 10 mg of active ingredient and with the following composition:

Claims (3)

1. Procedure for the preparation of compounds of the formula: there R 1 is a trifluoromethyl residue, R 2 and R 3 are together with the nitrogen atom they are attached to a morphol no residue and R4 is a 4-methyl-phenyl, 2,3 or 4-fluoro-phenyl, 4-methoxy-phenyl, 4-methyl 3-fluoro-phenyl, 2,4-difluoro-phenyl or 4- amino-phenyl; or R 1 is a trifluoromethyl residue, R 2 and R 3 are together with the nitrogen atom they are attached to a thiomorpholino residue or R2 is a methyl residue and R3 is a 2-methoxyethyl residue and R4 is a 4-methylphenyl residue; or Ri means a chlorine or fluorine atom or a methoxy acid residue, R2 and R 3 together with the nitrogen to which they are attached means a morphol no residue and R 4 means a 4-methyl-phenyl residue, characterized in that it comprises: A. To prepare compounds of formula I except those where R 4 is a 4-amlno phenyl residue, react a quinolone with the formula : is R 1 and R 4 have the same meaning as above except that R 4 cannot be a 4-amino-phenyl residue, with a compound of the formula: where R 2 and R 3 have the same meaning as above and Hal means a halogen atom, and then isolates the product; or B. For the preparation of compounds of formula I except those where R4 is a 4-amino phenyl residue, react a compound of formula: with an amine of the formula: where Ri, Rg, R3 and R4 have the same meaning as above except that R4 cannot be a 4-amino phenyl residue, and then isolates the product; or C. To prepare a compound of formula I where R 4 is a 4-amino phenyl residue, reduce 4-[(2-(4-nitro-phenyl) 5-trifluoromethyl 4-quinolyl) oxyacetyl] morpholine and then isolate the product. 2. Method according to claim 1 for the preparation of compounds of formula I where Ri means a trifluoromethyl residue, R2 and R3 together with the nitrogen atom to which they are bound form a morpholine ring and R4 means a 4-methyl-phenyl-, 4-chloro-phenyl-, 4-fluoro- phenyl-, 4-methoxy-phenyl-, 4-methyl 3-fluoro-phenyl- or 2,4-difluoro-phenyl residue. 3. Method according to claim 1 for the production of 4-[2-(4-methyl-phenyl) 5-trifluoromethyl 4-quinolyl) oxyacetyl] morpholine.